Quinazoline derivatives and pharmaceutical applications thereof

ABSTRACT

A quinazoline derivative having formula (1) and a pharmaceutically acceptable salt thereof: 
                 
 
wherein the ring A represents an aryl group,
         which derivative has a chymase inhibitory activity and suppresses the exacerbation of vascular permeability induced by chymase, and a pharmaceutical composition containing the same as an essential ingredient. These compounds are useful for treatment of allergic diseases, rheumatic diseases, and cardiac and circulatory system diseases which are due to the abnormal exacerbation of Angiotensin II production.

TECHNICAL FIELD

The present invention relates to a quinazoline derivative having achymase inhibitory activity and a pharmaceutically acceptable saltthereof and to a pharmaceutical composition and a chymase inhibitorhaving the same as an effective ingredient. The present invention alsorelates to a method for producing the quinazoline derivative and asynthesis intermediate thereof.

BACKGROUND ART

Chymase is known to be present in secretory granules of mast cells (MC),which are closely related to inflammation, as one type of inflammatorycell. Further, human chymase similarly is mainly present broadly in MCsin the skin, heart, vascular walls, intestines, and other tissue (MastCell Proteases in Immunology and Biology; Caughey, G. H., ed; MarcelDekker, Inc.: New York, 1995). Human MCs are known to increase withbronchial asthma, allergic dermatitis and other allergic diseases,arteriosclerosis (Kaartinen et al., Circulation, 1994, 90, 1669),myocardial infarction (Kovanen et al., Circulation, 1995, 92, 1084), andother circulatory system diseases and rheumatoid arthritis (Gotis-Grahamet al., Arthritis Rheum., 1997, 40, 479). Further, it has been reportedthat the genetic polymorphism of chymase is correlated to the onset ofeczema (Mao et al., Lancet, 1996, 348, 581). Human chymase producesangiotensin II (Ang II) specifically from angiotensin I (Ang I) in thesame way as an angiotensin converting enzyme. Ang II is closely relatedto regulation of the blood pressure, diuretic regulation, the migrationand proliferation of smooth muscle cells etc. in the cardiovascularsystem tissue, the growth of the extracellular matrix, and otherhypertrophy and remodeling of the cardiovascular system (HidekiOkunishi; Naibunpitsu-Tonyobyoka, 1996, 3(6), 535). Human chymase isreported to have the following actions due to its protease activity inaddition to production of Ang II: 1) degradation of the extracellularmatrix (Vartio et al., J. Biol. Chem., 1981, 256, 471), activation ofcollagenase (Kovanen et al., J. Biol. Chem., 1994, 269, 18134), andproduction of collagen (Kofford et al., J. Biol. Chem., 1997, 272,7127); 2) causing release of inflammatory cytokine, for example, releaseof TGF β1 from extracellular matrix (Taipale et al., J. Biol. Chem.,1995, 270, 4689) and production of IL-1β (Mizutani. et al., J. Exp.Med., 1991, 174, 821); and 3) activation of stem cell factor (SCF)causing differentiation and proliferation of MCs (Longley et al., Pro.Nat. Acad. Sci., 1997, 94, 9017). Further, rat MC chymase is known tocause degranulation of MCs through IgE receptors, release chemicalmediators such as histamine, partially hydrolyze the apolipoproteins oflow density lipoproteins (LDL) to make modified LDL incorporated intomacrophages, and convert the macrophages to foam cells (Mast CellProteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker,Inc.: New York, 1995).

On the other hand, low molecular chymase inhibitors have already beenshown in print (Protease Inhibitors; Barrett et. al., eds.; ElssevierScience B. V.: Amsterdam, 1986). Further, recently, as peptideinhibitors for human chymase, there have been α-keto acid derivatives(WO-A-93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738) andα,α-difluoro-β-keto acid derivatives (JP-A-9-124691), while aspeptide-mimetic inhibitors, there are trifluoromethylketone derivatives(WO-A-96-33974, JP-A-10-53579), and α,α-difluoro-β-keto acid derivatives(JP-A-10-7661), while as nonpeptide inhibitors, there have beenimidazolinedione derivatives (J. Med. Chem., 1997, 40, 2156),quinazoline derivatives (WO 97-11941), phenyl ester derivatives(JP-A-10-87567), etc. There are no examples however of commercializationas medicaments.

The above reports relating to chymase suggest that chymase plays animportant role in the process of inflammation, repair, and cure ofdamaged tissue. That is, it breaks down the extracellular matrix at theinflammatory tissue, releases and activates inflammatory cytokine,causes cell migration and proliferation, reproduces the extracellularmatrix, and makes the tissue repair. The excess reactions in thisprocess are believed to be linked to various diseases. Therefore, byinhibiting chymase and suppressing the exacerbation of vascularpermeability induced by chymase, utilization as a medicament forprevention and a medicament for treatment of allergic diseases such asbronchial asthma, cnidosis, atopic dermatitis, mastocytosis, scleriasis,rheumatic diseases such as arthritis, cardiac and circulatory systemdiseases arising due to abnormal exacerbation of Ang II production, forexample, cardiac insufficiency, hypercardia, stasis cardiac diseases,hypertension, arteriosclerosis, peripheral circulatory disorders,revasoconstriction after PCTA, diabetic renal disorders or non-diabeticrenal disorders, coronary diseases including myocardial infarction,angioendothelia, or vascular disorders accompanying arterialization oratheroma may be given as examples.

DISCLOSURE OF INVENTION

Accordingly, the object of the present invention is to provide acompound having a chymase inhibitory activity and capable of suppressingthe advance of vascular permeability induced by chymase and useful as apharmaceutical composition and a pharmaceutical composition containingthe same.

In accordance with the present invention, there is provided aquinazoline derivative having the following formula (1) and apharmaceutically acceptable salt thereof:

wherein, the ring A represents an aryl group

-   -   R¹ represents a hydroxyl group, an amino group, a C₁ to C₄ lower        alkylamino group which may be substituted with a carboxylic acid        group, a C₇ and C₁₀ lower aralkylamino group which may be        substituted with a carboxylic acid group, an amino group        acylated with a C₁ to C₄ lower aliphatic acid which may be        substituted with a carboxylic acid group, an amino group        acylated with an aromatic ring carboxylic acid which may be        substituted with a carboxylic acid group, an amino group        acylated with a heteroaromatic ring carboxylic acid which may be        substituted with a carboxylic acid group, an amino group        sulfonylated with a C₁ to C₄ lower alkanesulfonic acid which may        be substituted with a carboxylic acid group, an amino group        sulfonylated with an aromatic ring sulfonic acid which may be        substituted with a carboxylic acid group, an amino group        sulfonylated with a heteroaromatic ring sulfonic acid which may        be substituted with a carboxylic acid group, a C₁ to C₄ lower        alkyl group substituted with a carboxylic acid group, or a C₂ to        C₄ lower alkenyl group which may be substituted with a        carboxylic acid group.    -   R² and R³ may be the same or different and represent a hydrogen        atom, an unsubstituted or substituted C₁ to C₄ lower alkyl        group, a halogen atom, a hydroxyl group, a C₁ to C₄ lower        alkoxyl group, an amino group, an unsubstituted or substituted        C₁ to C₄ lower alkylamino group, an unsubstituted or substituted        C₇ to C₁₀ aralkylamino group, an amino group acylated with a C₁        to C₄ lower aliphatic acid which may be substituted with a        carboxylic acid group, an amino group acylated with an aromatic        ring carboxylic acid which may be substituted with a carboxylic        acid group, an amino group acylated with a heteroaromatic ring        carboxylic acid which may be substituted with a carboxylic acid        group, an amino group sulfonylated with a C₁ to C₄ lower        alkanesulfonic acid which may be substituted with a carboxylic        acid group, an amino group sulfonylated with an aromatic ring        sulfonic acid which may be substituted with a carboxylic acid        group, an amino group sulfonylated with a heteroaromatic ring        sulfonic acid which may be substituted with a carboxylic acid        group, or a carboxylic acid group or    -   when the ring A is a benzene ring, R¹ and R² may form, together        with the substituting benzene ring, a fused heterocyclic ring        which may be substituted with a carboxylic acid and in which the        carbon atom in the ring may form a carbonyl group and R³ is the        same as defined above; and    -   X represents a hydrogen atom, a C₁ to C₄ lower alkyl group, a C₁        to C₄ lower alkoxy group, a halogen atom, a hydroxyl group, an        amino group, or a nitro group.

The present compound has a human chymase inhibitory activity andsuppresses the exacerbation of vascular permeability induced by chymaseand is useful as a pharmaceutical composition for the prevention ortreatment of allergic diseases or rheumatic diseases caused by theincrease in mast cells or cardiac and circulatory system diseases due tothe abnormal exacerbation of angiotensin II production.

In accordance with the present invention, there is also provided apharmaceutical composition comprising, as an effective ingredient, theabove-mentioned quinazoline derivative or the pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable conventionalcarrier therefor.

In accordance with the present invention, there is further provided amethod for producing the quinazoline derivative and a synthesisintermediate thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (1), preferable examples of the aryl grouprepresented by the ring A are a benzene ring and a naphthalene ring.

Preferable examples of the C₁ to C₄ lower alkylamino group which may besubstituted with the carboxylic acid group and the C₇ to C₁₂ loweraralkylamino group which may be substituted with a carboxylic acid grouprepresented by R¹ are a methylamino group, an ethylamino group, apropylamino group, a butylamino group, a carboxymethylamino group, acarboxyethylamino group, a carboxypropylamino group, a carboxybutylaminogroup, a benzylamino group, a phenetylamino group, a phenylpropylaminogroup, a phenylbutylamino group, a carboxybenzylamino group, acarboxyphenetylamino group, a carboxyphenylpropylamino group, acarboxyphenylbutylamino group, etc.

Preferable examples of the amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group,the amino group acylated with an aromatic ring carboxylic acid which maybe substituted with a carboxylic acid group, and the amino groupacylated with a heteroaromatic ring carboxylic acid which may besubstituted with a carboxylic acid group represented by R¹ are aformylamino group, an acetylamino group, a propionylamino group, abutyrylamino group, a benzoylamino group, a naphthoylamino group, apyridinecarbonylamino group, a pyrrolecarbonylamino group, acarboxyacetylamino group, a carboxypropionylamino group, acarboxybutyrylamino group, a carboxybenzoylamino group, acarboxynaphthoylamino group, a carboxypyridinecarbonylamino group, acarboxypyrrolecarbonylamino group, etc.

Preferable examples of the amino group sulfonylated with a C₁ to C₄lower alkanesulfonic acid which may be substituted with a carboxylicacid group, the amino group sulfonylated with an aromatic ring sulfonicacid which may be substituted with a carboxylic acid group, and theamino group sulfonylated with a heteroaromatic ring sulfonic acid whichmay be substituted with a carboxylic acid group represented by R¹ are amethanesulfonylamino group, an ethanesulfonylamino group, apropanesulfonylamino group, a butanesulfonylamino group, abenzenesulfonylamino group, a naphthalenesulfonylamino group, apyridinesulfonylamino group, a pyrrolesulfonylamino group, acarboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, acarboxypropanesulfonylamino group, a carboxybutanesulfonylamino group, acarboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylaminogroup, a carboxypyridinesulfonylamino group, acarboxypyrrolesulfonylamino group, etc.

Preferable examples of the C₁ to C₄ lower alkyl group substituted with acarboxylic acid group represented by R¹ are an acetic acid group, apropionic acid group, a butyric acid group, a valeric acid group, etc.

Preferable examples of the C₂ to C₄ lower alkenyl group substituted witha carboxylic acid group represented by R¹ are an acrylic acid group, acrotonic acid group, etc.

Preferable examples of the unsubstituted or substituted C₁ to C₄ loweralkyl group represented by R² or R³ are a straight-chain alkyl groupsuch as a methyl group, an ethyl group, a n-propyl group, and a n-butylgroup and a branched alkyl group such as an isopropyl group, a sec-butylgroup, and a t-butyl group.

Preferable examples of the substituent group of the C₁ to C₄ lower alkylgroup are a carboxylic acid group, a halogen atom such as a fluorineatom and a chlorine atom, a C₁ to C₄ lower alkoxy group, an amino group,a methylamino group, a dimethylamino group, a carboxymethylamino group,a carboxyethylamino group, etc.

Preferable examples of the halogen atom represented by R² or R³ are afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Preferable examples of the C₁ to C₄ lower alkoxyl group represented byR² or R³ are a straight-chain alkyloxy group such as a methoxy group, anethoxy group, a n-propyloxy group, and a n-butoxy group and a branchedalkyloxy group such as an isopropyloxy group, a sec-butoxy group, and at-butoxy group.

Preferable examples of the unsubstituted or substituted C₁ to C₄ loweralkylamino group represented by R² or R³ are a methylamino group, anethylamino group, a propylamino group, a butylamino group, etc.

Preferable examples of the substituent group of the C₁ to C₄ loweralkylamino group are a carboxylic acid group, a halogen atom such as afluorine atom and a chlorine atom, a C₁ to C₄ lower alkoxyl group, etc.

Preferable examples of the unsubstituted or substituted C₇ to C₁₂ loweraralkylamino group represented by R² or R³ are a benzylamino group, aphenetylamino group, a phenylpropylamino group, a phenylbutylaminogroup, etc.

Preferable examples of the substituent group of the aralkylamino groupare a carboxylic acid group, a halogen atom such as a fluorine atom anda chlorine atom, a C₁ to C₄ lower alkoxyl group, etc.

Preferable examples of the amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a carboxylic acid group,the amino group acylated with an aromatic ring carboxylic acid which maybe substituted with a carboxylic acid group, and the amino groupacylated with a heteroaromatic ring carboxylic acid which may besubstituted with a carboxylic acid group represented by R² or R³ are aformylamino group, an acetylamino group, a propionylamino group, abutyrylamino group, a benzoylamino group, a naphthoylamino group, apyridinecarbonylamino group, a pyrrolecarbonylamino group, acarboxyacetylamino group, a carboxypropionylamino group, acarboxybutyrylamino group, a carboxybenzoylamino group, acarboxynaphthoylamino group, a carboxypyridinecarbonylamino group, acarboxypyrrolecarbonylamino group, etc.

Preferable examples of the amino group sulfonylated with a C₁ to C₄lower alkanesulfonic acid which may be substituted with a carboxylicacid group, the amino group sulfonylated with an aromatic ring sulfonicacid which may be substituted with a carboxylic acid group, and theamino group sulfonylated with a heteroaromatic ring sulfonic acid whichmay be substituted with a carboxylic acid group represented by R² or R³are a methanesulfonylamino group, an ethanesulfonylamino group, apropanesulfonylamino group, a benzenesulfonylamino group, anaphthalenesulfonylamino group, a pyridinesulfonylamino group, apyrrolesulfonylamino group, a carboxymethanesulfonylamino group, acarboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, acarboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylaminogroup, a carboxypyridinesulfonylamino group, acarboxypyrrolesulfonylamino group, etc.

Preferable examples of the fused heterocyclic ring which may besubstituted with a carboxylic acid and in which the carbon atom in thering may form a carbonyl group which R¹ and R² form together with thesubstituting benzene ring when the ring A is a benzene ring, are atetrahydroquinoline ring and a benzoxazine ring, for example, atetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, acarboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline,a carboxybenzodioxane, etc.

Preferable examples of the C₁ to C₄ lower alkyl group represented by Xare a straight-chain alkyl group such as a methyl group, an ethyl group,a n-propyl group, and a n-butyl group and a branched alkyl group such asan isopropyl group, a sec-butyl group, and a t-butyl group.

Preferable examples of the C₁ to C₄ lower alkoxyl group represented by Xare a straight-chain alkyloxy group such as a methoxy group, an ethoxygroup, a n-propyloxy group, and a n-butoxy group and a branched alkyloxygroup such as an isopropyloxy group, a sec-butoxy group, and a t-butoxygroup.

Preferable examples of the halogen atom represented by X, are a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

Further, examples of a pharmaceutically acceptable salts are an acidsalt such as a hydrochloric acid salt, a methanesulfonic acid salt, anda trifluoroacetic acid salt and an alkali metal salt such as a sodiumsalt and a potassium salt.

The quinazoline derivative having the formula (1) according to thepresent invention may, for example, be synthesized by the followingSynthesis Method (A) or (B).

Synthesis Method (A)

A compound having the formula (2):

wherein the ring A is the same as defined above and R¹′, R²′ and R³′represent R¹, R² and R³, which may be protected with a protecting group,respectively, and R¹, R² and R³ represent the same as defined above

-   -   is reacted with an anthranilic acid derivative having the        formula (3):    -    wherein X′ represents X, which may be protected with a        protecting group, and X represents the same as defined above    -   using the method described, for example, in JP-A-6-199839 to        obtain a sulfonylurea derivative having the formula (4):    -    wherein the ring A, R¹′, R²′, R³′ and X′ represent the same as        defined above,    -   then, a condensing agent for example, 1,1′-carbonyldiimidazole        (hereinafter referred to as CDI) is used to obtain the        quinazoline ring, and if necessary, the protecting groups of R¹,        R², R³ and X are deprotected.

In this reaction, when R¹, R² or R³ represents a group containing ahydroxyl group, an amino group, or a carboxylic acid group, R¹, R² or R³may be optionally protected by a protecting group such as abenzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, anallyl group, a t-butyl group, etc. When X represents a hydroxyl group oran amino group, X may be optionally protected with a protecting groupsuch as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzylgroup, an allyl group, a t-butyl group, etc.

The compound having the formula (2) used in this reaction includes acommercially available or known compound or a compound which can besynthesized by a known method may be used. For example, using thesynthesis method described in the specification of European Patent No.0269141, it is possible to use a compound which can be synthesized fromthe corresponding sulfonamide derivative using chlorosulfonylisocyanate. For example, it is possible to use3-allyloxycarbonyl-methylbenzenesulfonyl isocyanate,4-allyloxycarbonyl-methylbenzenesulfonyl isocyanate,4-allyloxybenzenesulfonyl isocyanate, etc.

As the anthranilic acid derivative having the formula (3) used for thisreaction, a commercially available or known compound or a compound whichcan be synthesized by a known method may be used. For example,anthranilic acid, 4-chloroanthranilic acid, 4-methoxyanthranilic acid,5-chloroanthranilic acid, 4-hydroxyanthranilic acid, etc. may be used.

The reaction to obtain the quinazoline ring from the sulfonylureaderivative having the formula (4) may be carried out using an aprotonicsolvent such as, for example, an ether solvent such as tetrahydrofuranand dioxane, a halogen-containing solvent such as methylene chloride, ordimethylformamide etc. at a temperature of −50° C. to 50° C., preferably−20° C. to room temperature. Further, for the cyclization reaction, itis possible to use an ordinary condensing agent which includes, forexample, CDI, dicyclohexylcarbodiimide, and similar carbodiimidecompounds, mixed anhydrides, etc. The deprotecting reaction can becarried out by an ordinary method using hydrolysis with an acid oralkali, reduction or oxidation etc.

Synthesis Method (B)

A compound having the formula (5):

wherein the ring A, R¹′, R²′ and R³′ represent the same as defined above

-   -   is condensed with an anthranilic acid derivative having the        formula (6):    -    wherein X′ represents the same as defined above, Ph represents        a phenyl group, and R⁴ represents a protecting group of the        carboxyl group, which is specifically a group capable of being        released by hydrolysis or hydrogenolysis, such as, for example,        a methyl group, an ethyl group, or a benzyl group    -   using, for example, 1,8-diazabicyclo[5,4,0]-7-undecene        (hereinafter referred to as DBU) to form a sulfonylurea        derivative having the formula (7):    -    wherein the ring A, R¹′, R²′, R³′, R⁴ and X′ are the same as        defined above,    -   which is then hydrolyzed with an alkali or hydrogenolyzed to        derive a corresponding carboxylic acid represented by the        formula (4), then the quinazoline ring is obtained and        optionally the protecting groups of R¹, R², R³ and X are        deprotected, in the same way as in Synthesis Method (A). In this        reaction, when R¹, R² or R³ represents a group containing a        hydroxyl group, an amino group, or a carboxylic acid group, R¹,        R² or R³ may be optionally protected by a protecting group such        as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl        group, an allyl group, a t-butyl group, etc. When X represents a        hydroxyl group or an amino group, X may be optionally protected        with a protecting group such as a benzyloxycarbonyl group, a        t-butoxycarbonyl group, a benzyl group, an allyl group, a        t-butyl group, etc.

As the compound having the formula (5) used in the reaction, acommercially available or known compound or a compound which can besynthesized by a known method may be used. For example,3-hydroxybenzenesulfonamide, 2-aminobenzenesulfonamide,3-aminobenzenesulfonamide, 4-aminobenzenesulfonamide,(±)-2-(4-aminosulfonylphenyl)butyric acid,3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide,4-benzyloxycarbonylamino-3-chlorobenzenesulfonamide,4-amino-3,5-dichlorobenzenesulfonamide,3-benzyloxycarbonylamino-4-methylbenzenesulfonamide,4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide,3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide,4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide,3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide,3-acetamide-4-methoxybenzenesulfonamide,3-(3-aminosulfonyl)phenylacrylic acid t-butylester,3-amino-4-methoxybenzenesulfonamide,4-methoxy-3-methylsulfonylaminobenzenesulfonamide,3-carboxy-4-hydroxy-2-naphthalenesulfonamide,4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide,(±)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide,(±)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazine-6-sulfonamide, etc. may beused.

As the anthranilic acid derivative having the formula (6) used in thisreaction, a commercially available or known compound or a compound whichcan be synthesized by a known method may be used. For example, methyl4-chloro-2-N-phenoxycarbonylanthranilate, ethyl4-chloro-2-N-phenoxycarbonylanthranilate, benzyl4-chloro-2-N-phenoxycarbonylanthranilate, methyl5-chloro-2-N-phenoxycarbonylanthranilate, ethyl5-chloro-2-N-phenoxycarbonylanthranilate, benzyl5-chloro-2-N-phenoxycarbonylanthranilate, methyl4-methoxy-2-N-phenoxycarbonylanthranilate, ethyl4-methoxy-2-N-phenoxycarbonylanthranilate, benzyl4-methoxy-2-N-phenoxycarbonylanthranilate, methyl4-hydroxy-2-N-phenoxycarbonylanthranilate, ethyl4-hydroxy-2-N-phenoxycarbonylanthranilate, benzyl4-hydroxy-2-N-phenoxycarbonylanthranilate, etc. may be used.

The reaction for obtaining the compound having the formula (5) and theanthranilic acid derivative having the formula (6) condense to obtain asulfonylurea derivative having the formula (7), may be carried out usingan aprotic solvent, for example, an ether solvent such astetrahydrofuran or dioxane, a halogen-containing solvent such asmethylene chloride, or dimethylformamide etc. at a temperature of −50°C. to 50° C., preferably −20° C. to room temperature. Further, as theusable for the condensation reaction, an organic strong base such asDBU, inorganic bases such as potassium carbonate, sodium carbonate,potassium hydroxide, and sodium hydroxide, or metal bases such as sodiumhydride may be used.

In the reaction for alkali hydrolysis or hydrogenolysis of thesulfonylurea derivative having the formula (7) thus obtained to obtainthe sulfonylurea derivative having the formula (4), ordinary hydrolysisconditions or hydrogenolysis conditions for esters may be used.

Note that the above reaction may be carried out while protecting thefunctional groups not involved in the reaction. According to the type ofthe protecting group, the protection is removed by chemical reduction orother ordinary protection-removing reactions. For example, when theprotecting group is a t-butyl group or t-butoxycarbonyl group,trifluoroacetic acid may be used, while when it is an allyl group,palladium catalysts such as tetrakis(triphenylphosphine)palladium (0)may be used.

The compound having the formula (1), wherein R¹ represents an aminogroup acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a carboxylic acid, an amino group acylated with anaromatic ring carboxylic acid which may be substituted with a carboxylicacid and an amino group acylated with an heteroaromatic ring carboxylicacid which may be substituted with a carboxylic acid, can be obtainedfrom the compound having the formula (1), wherein R¹ represents an aminogroup, by acylating the same with carboxylic acid, carboxylic acidchloride, carboxylic acid anhydride using an ordinary method.

The compound having the formula (1), wherein R¹ represents an aminogroup sulfonylated with a C₁ to C₄ lower alkane sulfonic acid which maybe substituted with a carboxylic acid, an amino group sulfonylated withan aromatic ring sulfonic acid which may be substituted with acarboxylic acid and an amino group sulfonylated with an heteroaromaticring sulfonic acid which may be substituted with a carboxylic acid, canbe obtained from the compound having the formula (1), wherein R¹represents an amino group, by sulfonylating the same with sulfonic acidor sulfonic acid chloride using an ordinary method.

The product obtained according to the above-mentioned processes can bepurified by a method such as recrystallization or column chromatography.

If necessary, the compounds having the formula (1) of the presentinvention obtained according to the above-mentioned processes can eachbe reacted with one of various acids or basis to convert the compoundinto their salt. Exemplary acids usable for the conversion of thecompound having the formula (1) into their salts can include inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid; and organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid,citric acid, lactic acid, maleic acid, fumaric acid, tartaric acid,acetic acid, adipic acid, palmitic acid and tannic acid. Exemplaryusable basis for the conversion of the compound having the formula (1)into their salts can include sodium hydroxide, lithium hydroxide andpotassium hydroxide.

Further, the compounds having the formula (1) according to the presentinvention include those containing asymmetric centers. Each racemicmixture can be isolated by one or more of various methods, whereby asingle optically-active substance can be obtained. Usable methodsinclude, for example:

-   -   (1) Isolation by optically active column.    -   (2) Isolation by recrystallization subsequent to conversion into        a salt with an optically active acid or base.    -   (3) Isolation by a combination of the above methods (1) and (2).

The quinazoline derivative of the present invention has an inhibitoryactivity with respect to human chymase. Further, it suppresses theexacerbation of vascular permeability caused by chymase. Further, itexhibits a sufficient half-life in human plasma. Therefore, as aninhibitor for mast cell chymase including human chymase, it is expectedto be useful as a medicament for the prevention or treatment of cardiacand circulatory system diseases due to abnormal production of Ang II andfor the prevention or treatment of allergic diseases and rheumatoidarthritis.

To use the effective ingredient of the present invention as apharmaceutical composition for the prevention or treatment of cardiacand circulatory system diseases due to the abnormal exacerbation of AngII production and allergic diseases and rheumatic diseases which arerelated to mast cells, one or more of the compounds of the presentinvention may be mixed and formed into a form suitable for use in themethod of administration by an ordinary method. Examples of preparationforms for oral administration include capsules, tablets, granules, finegranules, syrups, dry syrups, and other preparations, while examples ofpreparation forms for non-oral administration include injections andbesides suppositories such as rectal suppositories and vaginalsuppositories, transnasal preparations such as sprays and ointments, andpercutaneous preparations such as tapes for percutaneous absorption.

The clinical dose of the compound according to the present inventionvaries according to the diseased condition, degree of seriousness, age,presence of complications, etc. and also varies according to itspreparation form. In the case of oral administration, however, it may bedosed usually, in terms of effective ingredients, as 1 to 1000 mg peradult per day. In the case of non-oral administration, it is sufficientto administer {fraction (1/10)} to ½ the amount of the case of oraladministration. These dosages can be suitably adjusted according to theage, the diseased condition, and the like of the patient to be dosed.

The toxicity of the compound according to the present invention is low.The acute toxicity values LD₅₀ at 24 hours after oral administration to5-week old male mice were 1 g/kg or more.

EXAMPLES

The present invention will now be further explained by, but is by nomeans limited to, the following Examples, but the scope of the inventionis not limited to these Examples needless to say.

Example 1 Synthesis of7-chloro-3-(3-hydroxybenzenesulfonyl)-2,4(1H,3H)-quinazolinedione(Compound 1)

Following the Synthesis Method (B), 938 mg (5.42 mmol) of3-hydroxybenzenesulfonamide was dissolved in 40 ml of tetrahydrofuran,then 892 μl (5.96 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene(hereinafter referred to as DBU) was added dropwise. The reactionsolution was stirred at room temperature for 15 minutes, then 1.66 g(5.42 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate was addedand the mixture was stirred at room temperature overnight. An excessamount of water was poured into the reaction solution, then the mixturewas made acidic with hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with water and saturated saline, dried overanhydrous magnesium sulfate, and concentrated. The crude product thusobtained was purified by silica gel column chromatography (0% to 5%methanol/dichloromethane) to obtain 1.23 g (yield 59%) of methyl4-chloro-2-{([(3-hydroxybenzenesulfonylamino)carbonyl]amino} benzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.91 (3H, s),7.02 (1H, m), 7.09 (1H, m), 7.34 (1H, t), 7.57 (2H, m), 7.89 (1H, d),8.38 (1H, d), 10.94 (1H, s). Next, the 1.23 g (3.2 mmol) of the compoundthus obtained was dissolved in 20 ml of methanol, then 10 ml of 2Nsodium hydroxide aqueous solution was added dropwise. The reactionsolution was stirred at room temperature for 15 minutes, then an excessamount of water was added and the mixture was made acidic withhydrochloric acid. This was then stirred to cause crystals toprecipitate which were then obtained by filtration and dried to obtaincarboxylic acid. The product thus obtained was dissolved in 50 ml oftetrahydrofuran (hereinafter referred to as THF), then 434 mg (2.68mmol) of CDI was added under ice cooling and the mixture was stirred for30 minutes. The reaction solution was diluted with ethyl acetate, washedwith water and saturated saline, and dried over anhydrous magnesiumsulfate, then concentrated to obtain a crude product. The crude productwas purified by silica gel column chromatography (ethylacetate:n-hexane=1:2) to obtain 230 mg (yield 20%: 2 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.12 (2H, s),7.24 (1H, d), 7.48 (1H, t), 7.58 (2H, s), 7.85 (1H, d), 10.28 (1H, s),11.63 (1H, s).

Example 2 Synthesis of3-(2-aminobenzenesulfonyl)-7-chloro-2,4(1H,3H-quinazolinedione (Compound2)

2.7 g (15.7 mmol) of 2-aminobenzenesulfonamide and 4.8 g (15.7 mmol) ofmethyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the sameway as Example 1 to obtain 3.2 g (yield 58%: 3 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.46 (2H, s),6.65 (1H, t), 6.81 (1H, d), 7.12 (1H, s), 7.23 (1H, d), 7.34 (1H, t),7.76 (1H, d), 7.86 (1H, d).

Example 3 Synthesis of7-chloro-3-(2-methylsulfonylaminobenzenesulfonyl)-2,4(1H,3H)-quinazolinedione(Compound 3)

22 mg (0.06 mmol) of Compound 2 was dissolved in 200 μl of pyridine,11.6 μl (0.15 mmol) of methanesulfonyl chloride was added dropwise, thenthe resultant mixture was stirred at room temperature overnight. Anexcess amount of water was added to the reaction solution and themixture was extracted with ethyl acetate. The organic layer was washedwith 1N aqueous hydrochloric acid solution and saturated saline, thendried over anhydrous magnesium sulfate and concentrated to obtain acrude product. The crude product was crystallized from diethyl ether toobtain 16 mg (0.04 mmol) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 3.61 (3H, s), 7.10 (1H, d), 7.20 (1H, d), 7.74 (1H, d),7.82-7.90 (4H, m), 8.34 (1H, d), 11.70 (1H, 9).

Example 4 Synthesis of3-(4-aminobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 4)

2.7 g (15.7 mmol) of 4-aminobenzenesulfonamide and 4.8 g (15.7 mmol) ofmethyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the sameway as Example 1 to obtain 7.9 g (yield 94%) of methyl2-{[(4-aminobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.59 (3H, s),5.37 (2H, s), 6.45 (2H, d), 6.83 (1H, dd), 7.41 (2H, d), 7.81 (1H, d),8.66 (1H, d), 9.64 (1H, s).

Then, from the resultant 7.9 g (14.8 mmol) of sulfonylurea product, inthe same way, 4.3 g (yield 83%: 2 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆); 2.33 (3H, s),6.93 (1H, m), 7.13 (1H, d), 7.23-7.26 (3H, m), 7.30 (1H, s), 7.86 (1H,d), 11.61 (1H, s).

Example 5 Synthesis of3-(3-carboxymethyl-benzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 5)

Following the Synthesis Method (A), 3.27 g (11.6 mmol) of3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100ml of anhydrous THF, then 1.98 g (11.5 mmol) of 4-chloroanthranilic acidwas added and the mixture was stirred at room temperature for 2 hours.The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol)of CDI was added and the resultant mixture was stirred under ice coolingfor 30 minutes. An excess amount of water was poured into the reactionsolution, then the mixture was extracted with ethyl acetate. The organiclayer was washed, dried, and concentrated to obtain a crude product.This was crystallized with a small amount of ethyl acetate to obtain 2.0g (yield 40%) of3-(3-allyloxycarbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione.The allyl product thus obtained was dissolved in 100 ml of a formicacid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. Thereactor was shaded from light and under nitrogen atmosphere, then 700 mgof tetrakis(triphenylphosphine)palladium (0) was added and the resultantmixture was stirred while shaded at room temperature overnight. Thereaction solution was concentrated in vacuo and the solid obtained waswashed with methylene chloride to obtain 1.47 g (yield 81%) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.76 (2H, s),7.13 (1H, s), 7.24 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H, d), 8.05 (2H,s), 12.50 (1H, br).

Example 6 Synthesis of3-(4-carboxymethyl-benzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 6)

1.10 g (3.95 mmol) of 4-allyloxycarbonylmethylbenzenesulfonyl isocyanateand 678 mg (3.95 mmol) of 4-chloroanthranilic acid were treated in thesame way as in Example 5 to obtain 657 mg (yield 38%) of3-(4-allyloxycarbonylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione.538 mg (1.24 mmol) thereof was treated in the same way to obtain 342 mgof the above-identified compound (yield 70%). Properties: colorlesscrystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆):3.75 (2H, s), 7.13 (1H, s), 7.23 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H,d), 8.05 (2H, s), 12.07 (2H, br).

Example 7 Synthesis of(±)-2-{4-[(7-chloro-2,4(1H,3H)-quinazolin-3-yl)sulfonyl]phenyl}butyricacid (Compound 7)

1.02 g (3.41 mmol) of t-butyl(±)-2-(4-amino-sulfonylphenyl)butyrate acidand 1.04 g (3.41 mmol) of methyl4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way asExample 1 to obtain 1.46 g (yield 84%) of methyl2-[({4-[1-(t-butoxycarbonyl)propyl]benzenesulfonylamino}carbonyl)amino]-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃):0.89 (3H, t), 1.38(9H, s), 1.69-1.76 (1H, m), 2.03-2.10 (1H, m), 3.42 (1H, t), 3.94 (3H,s), 7.04 (1H, d), 7.47 (2H, d), 7.93 (1H, d), 8.01 (2H, d), 8.45 (1H,br), 11.04 (1H, br).

Next, 4.3 ml (8.6 mmol) of 2N sodium hydroxide aqueous solution was usedto similarly form carboxylic acid in an amount of 1.43 g and 463 mg(2.86 mmol) of CDI was used to obtain 970 mg (yield 71%: 2 steps) oft-butyl(±)-2-{4-[(7-chloro-2,4(1H,3H)-quinazolin-3-yl)sulfonyl]phenyl}butyrate.

Further, the t-butylester thus obtained was dissolved in 5 ml ofdichloromethane, then 5 ml of trifluoroacetic acid was added and theresultant mixture was stirred at room temperature for 40 minutes. Thereaction solution was concentrated in vacuo and the resultant crudeproduct was washed with a small amount of diethyl ether to obtain 820 mgof the above-identified compound (yield 96%). Properties: colorlesscrystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆):0.84 (3H, t), 1.67-1.75 (1H, it), 1.98-2.05 (1H, m), 3.62 (1H, t), 7.11(1H, s), 7.24 (1H, d), 7.61 (2H, d), 7.86 (1H, d), 8.13 (2H, d), 11.62(1H, s).

Example 8 Synthesis of3-(3-amino-4-chlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 8)

1.0 g (2.93 mmol) of 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamideand 1.18 g (2.93 mmol) of benzyl4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way asExample 1 to obtain 1.43 g (yield 78%) of benzyl2-{[(3-benzyloxycarbonylamino-4-chlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorlessamorphous, PMR (δ ppm, DMSO-d₆): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H,dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d),8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, s). 1.38 g (2.20 mmol) thereofwas dissolved in 50 ml of THF, then 200 mg of palladium-carbon (10%) wasadded and the mixture was stirred under a hydrogen flow for 2 hours. Thereaction mixture was filtered with Celite to remove thepalladium-carbon, then the filtrate was concentrated in vacuo to obtaina carboxylic acid. The product obtained was suspended in 50 ml of THF,then 356 mg (2.20 mmol) of CDI was added under ice cooling and theresultant mixture was treated in the same way as Example 1 to obtain 560mg (yield 66%: 2 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 6.00 (2H, s), 7.12 (1H, s), 7.26 (2H, t), 7.48 (1H, d), 7.66(1H, s), 7.86 (1H, d), 11.76 (1H, br).

Example 9 Synthesis of3-(4-amino-3.5-dichlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 9)

1.06 g (4.40 mmol) of 4-amino-3,5-dichlorobenzenesulfonamide and 1.34 g(4.40 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as Example 1 to obtain 905 mg (yield 44%) ofmethyl2-{[(4-amino-3,5-dichlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 3.87 (3H, s),6.59 (2H, br), 7.22 (1H, dd), 7.72 (2H, s), 7.93 (1H, d), 8.24 (1H, d),10.17 (1H, s).

Then, from 905 mg (2.0 mmol) of the resultant sulfonylurea product, inthe same way, 660 mg (yield 82%: 2 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.80 (2H, s),7.12 (1H, s), 7.24 (1H, d), 7.86 (1H, d), 7.92 (2H, s), 11.63 (1H, br).

Example 10 Synthesis of3-(3-amino-4-methylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 10)

960 mg (3.00 mmol) of3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Example 8 to obtain 1.14 g (yield 62% of benzyl2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.30 (3H, s),5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33-7.48 (1H, m), 7.63 (1H,d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H,s), 12.20 (1H, br).

Then, from 1.14 g (1.87 mmol) of the resultant sulfonylurea product, inthe same way, 190 mg (yield 27%: 2 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 2.12 (3H, s),5.47 (2H, s), 7.12 (1H, s), 7.16-7.25 (3H, m), 7.38 (1H, s), 7.85 (1H,d), 11.58 (1H, s).

Example 11 Synthesis of3-[(3-carboxymethylaminophenyl)sulfonyl]-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 11)

1.62 g (5.65 mmol) of 3-t-butoxycarbonyl-methylaminobenzenesulfonamideand 1.73 g (5.65 mmol) of methyl4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way asin Example 7 to obtain 209 mg (yield 9%: 4 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.86 (2H, s),6.88 (1H, s), 7.12 (1H, s), 7.24 (1H, d), 7.30-7.38 (3H, m), 7.86 (1H,d), 11.61 (1H, br).

Example 12 Synthesis of3-(3-aminobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 12)

3.5 g (12.9 mmol) of 3-t-butoxycarbonylamino-benzenesulfonamide and 3.9g (12.8 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 7 to obtain 2.2 g (yield 49%: 4steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 5.72 (2H,s), 6.87 (1H, d), 7.12 (1H, s), 7.23-7.27 (2H, m), 7.33 (1H, s), 7.86(1H, d), 11.61 (1H, s).

Example 13 Synthesis of2-{3-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]phenylaminocarbonyl}propionicacid (Compound 13)

100 mg (0.28 mmol) of Compound 12 was dissolved in 5 ml of THF, 100 mg(1.0 mmol) of succinic anhydride was added, and the resultant mixturewas heated and refluxed for 3 hours. The reaction solution wasconcentrated in vacuo and the crude product thus obtained wascrystallized with ethyl acetate-diethyl ether to obtain 120 mg (yield96%) of the above-identified compound. Properties: colorless crystal,Melting point: 187-188° C., PMR (δ ppm, DMSO-d₆): 2.54 (2H, d), 2.59(2H, d), 7.12 (1H, s), 7.24 (1H, d), 7.59 (1H, t), 7.80 (1H, d), 7.86(1H, d), 7.96 (1H, d), 8.41 (1H, s), 10.40 (1H, s), 11.63 (1H, br),12.10 (1H, br).

Example 14 Synthesis of3-{3-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]phenyl}acrylicacid (Compound 14)

1.54 g (5.44 mmol) of t-butyl 3-(3-aminosulfonyl)phenylacrylate and 1.66g (5.44 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 7 to obtain 2.18 g (yield 81%) ofmethyl2-({[3-(3-t-butoxy-3-oxo-1-propenyl)benzenesulfonylamino]carbonyl}amino)-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.53 (9H, s), 3.95(3H, s), 6.46 (1H, d), 7.05 (1H, d), 7.55 (1H, m), 7.57 (1H, d), 7.72(1H, m), 7.93 (1H, m), 8.04 (1H, m), 8.27 (1H, s), 8.46 (1H, d), 11.05(1H, br).

Then, from 2.18 g (4.4 mmol) of the resultant sulfonylurea product, inthe same way, 698 mg (yield 37%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.65 (1H, d),7.12 (1H, s), 7.25 (1H, d), 7.69 (1H, d), 7.72 (1H, t), 7.87 (1H, d),8.12 (2H, q), 8.37 (1H, s), 11.64 (1H, s).

Example 15 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]salicylic acid(Compound 15)

1.0 g (3.66 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and1.12 g (3.66 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilatewere treated in the same way as in Example 7 to obtain 1.79 g (yield100%) of methyl2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 1.57 (9H, s),3.87 (3H, s), 7.14 (1H, d), 7.40-7.45 (2H, m), 7.85 (1H, d), 7.92 (1H,d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, s).

Then, from 1.78 g (3.66 mmol) of the resultant sulfonylurea product, inthe same way, 370 mg (yield 25%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.13 (1H, s),7.26 (1H, d), 7.69 (1H, d), 7.87 (1H, d), 8.01 (1H, d), 11.67 (1H, s).

Example 16 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]salicylic acidmonosodium salt (Compound 16)

50 mg (0.13 mmol) of Compound 15 was suspended in approximately 1 ml ofTHF, then 126 μl of 1N sodium hydroxide aqueous solution was addeddropwise. The solution was confirmed to have become uniform, then 30 mlof water was added and the mixture freeze-dried to quantitatively obtainthe above-identified compound in an amorphous state in an amount of 52mg. Properties: colorless amorphous, PMR (δ ppm, CD₃OD): 7.11 (1H, s),7.19 (1H, d), 7.58 (1H, d), 7.63 (1H, s), 7.92 (1H, d), 8.03 (1H, d).

Example 17 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid(Compound 17)

2.84 g (6.99 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 2.67 g(6.99 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 8 to obtain 3.74 g (yield 77%) ofbenzyl2-{[(3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 1.54 (9H, s),5.19 (2H, s), 5.34 (2H, s), 7.05 (1H, m), 7.34-7.58 (10H, m), 7.60 (1H,d), 7.90 (1H, d), 7.98 (1H, d), 8.50 (1H, br), 8.62 (1H, s), 10.00 (1H,br), 10.41 (1H, s).

Then, from 3.74 g (5.39 mmol) of the resultant sulfonylurea, in the sameway, 690 mg (yield 30%: 2 steps) of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilate wasobtained, then this was subjected to a similar debutylation reaction toobtain 503 mg (yield 84%) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 7.14 (1H, s), 7.18 (1H, d), 7.25 (1H, d), 7.59 (1H, s), 7.87(1H, d), 7.89 (1H, d), 11.62 (1H, s).

Example 18 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acidmonosodium salt (Compound 18)

50 mg (0.13 mmol) of Compound 17 was suspended in approximately 1 ml ofTHF, then 126 μl of 1N sodium hydroxide aqueous solution was addeddropwise. The solution was confirmed to have become uniform, then 30 mlof water was added and the mixture was freeze-dried to quantitativelyobtain the above-identified compound in an amorphous state in an amountof 52 mg. Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆):7.11-7.22 (3H, m), 7.37 (1H, s), 7.83 (1H, d), 7.91 (1H, d).

Example 19 Synthesis of3-(4-hydroxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 19)

1.50 g (7.03 mmol) of 4-allyloxybenzenesulfonyl isocyanate and 1.2 g(7.03 mmol) of 4-chloroanthranilic acid were treated in the same way asin Example 5 to obtain 1.5 g (yield 53%) of3-(4-allyloxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. 500mg (1.27 mmol) thereof was similarly treated to obtain 405 mg of theabove-identified compound (yield 90%). Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.98 (2H,d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 8.00 (2H, d), 11.25 (1H,br).

Example 20 Synthesis of4-[(2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]salicylic acid (Compound20)

618 mg (2.26 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and613 mg (2.26 mmol) of methyl 2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 792 mg (yield 78%) ofmethyl2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}benzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.60 (9H, s), 3.97(3H, s), 7.09 (1H, t), 7.49-7.52 (2H, m), 7.65 (1H, d), 7.90 (1H, d),8.01 (1H, dd), 8.33 (1H, d), 10.98 (1H, s), 11.18 (1H, s).

Then, from 790 mg (1.75 mmol) of the resultant sulfonylurea product, inthe same way, 100 mg (yield 8%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.13 (1H, d),7.22 (1H, t), 7.63-7.69 (3H, m), 7.87 (1H, d), 8.01 (1H, d), 11.57 (1H,s).

Example 21 Synthesis of5-[7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]salicylic acid(Compound 21)

320 mg (1.17 mmol) of 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and447 mg (1.17 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilatewere treated in the same way as in Example 17 to obtain 611 mg (yield93%) of benzyl2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.62 (9H, s), 5.35(2H, s), 7.01-7.05 (2H, m), 7.37-7.41 (5H, m), 7.96 (1H, d), 8.10 (1H,dd), 8.46-8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).

Then, from 611 mg (1.09 mmol) of the resultant sulfonylurea product, inthe same way, 114 mg (yield 33%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.11 (1H, s),7.19 (1H, d), 7.24 (1H, d), 7.86 (1H, d), 8.20 (1H, d), 8.56 (1H, s),11.57 (1H, s).

Example 22 Synthesis of3-(3-acetamide-4-methoxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 22)

500 mg (2.19 mmol) of 3-acetamide-4-methoxybenzenesulfonamide and 836 mg(2.19 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 8 to obtain 812 mg (yield 70%) ofbenzyl2-{[(3-acetylamino-4-methoxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.12 (3H, s),3.93 (3H, s), 5.36 (2H, s), 7.20 (1H, d), 7.24 (1H, d), 7.36-7.48 (5H,m), 7.69 (1H, d), 7.96 (1H, d), 8.24 (1H, s), 8.67 (1H, s), 9.39 (1H,s), 10.25 (1H, s), 12.11 (1H, br).

Then, from 611 mg (1.09 mmol) of the resultant sulfonylurea product, inthe same way, 250 mg (yield 39%: 2 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 2.12 (3H, s),3.95 (3H, s), 7.12 (1H, s), 7.23 (1H, d), 7.30 (1H, d), 7.85 (1H, d),7.89 (1H, d), 8.80 (1H, s), 9.42 (1H, s), 11.59 (1H, br).

Example 23 Synthesis of3-(3-amino-4-methoxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione(Compound 23)

400 mg (1.40 mmol) of3-t-butoxycarbonylamino-4-methoxybenzenesulfonamide and 533 mg (1.40mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Example 17 to obtain 86 mg (yield 16%: 4 steps) ofthe above-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.81 (3H, s),7.26-7.37 (5H, m), 7.77 (1H, s), 7.90 (1H, d), 7.94 (1H, d), 11.73 (1H,s).

Example 24 Synthesis of7-chloro-3-(4-methoxy-3-methylsulfonylaminobenzenesulfonyl)-2,4(1H,3H)-quinazolinedione(Compound 24)

500 mg (1.89 mmol) of 4-methoxy-3-methylsulfonylaminobenzenesulfonamideand 722 mg (1.89 mmol) of benzyl4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way asin Example 8 to obtain 888 mg (yield 83%) of benzyl2-({[(4-methoxy-3-methylsulfonylamino)benzenesulfonylamino]carbonyl}amino)-4-chlorobenzoate. Properties: colorlessamorphous, PMR (δ ppm, DMSO-d₆): 2.12 (3H, s), 3.93 (3H, s), 5.36 (2H,s), 7.20 (1H, d), 7.24 (1H, d), 7.36-7.48 (5H, m), 7.69 (1H, d), 7.96(1H, d), 8.24 (1H, s), 8.67 (1H, s), 9.39 (1H, s), 10.25 (1H, s), 12.11(1H, br).

Then, from 880 mg (1.55 mmol) of the resultant sulfonylurea product, inthe same way, 620 mg (yield 85%: 2 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. C3 (decomposition), PMR (δ ppm, DMSO-d₆): 3.04 (3H, s),3.94 (3H, s), 7.11 (1H, s), 7.23 (1H, d), 7.34 (1H, d), 7.86 (1H, d),7.99 (1H, d), 8.10 (1H, s).

Example 25 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-1-hydroxy-naphthalene-2-carboxylicacid (Compound 25)

323 mg (1.00 mmol) of3-t-butoxycarbonyl-4-hydroxy-1-naphthalenesulfonamide and 381 mg (1.00mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated inthe same way as in Example 17 to obtain 447 mg (yield 73%) of4-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-1-hydroxy-2-naphthalenecarboxylicacid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm,DMSO-d₆): 1.66 (9H, s), 5.34 (3H, s), 6.98 (1H, d), 7.35-7.48 (5H, m),7.66 (1H, m), 7.81 (1H, m), 7.89 (1H, d), 8.37 (2H, m), 8.44 (1H, s),8.71 (1H, d), 10.02 (1H, br), 12.52 (1H, br).

Then, from 445 mg (0.72 mmol) of the resultant sulfonylurea product, inthe same way, 56 mg (yield 18%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.08 (1H, s),7.20 (1H, d), 7.63 (1H, t), 7.77 (1H, t), 7.84 (1H, d), 8.42 (1H, d),8.51 (1H, d), 8.75 (1H, s), 11.57 (1H, s).

Example 26 Synthesis of 5-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-ylsulfonyl]anthranilic acid (Compound 26)

834 mg (2.05 mmol) of4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide and 783 mg(2.05 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 1.18 g (yield 83%) ofbenzyl 2-{[(4-benzyloxycarbonylamino-3-tbutoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate.Properties: colorless amorphous, PMR (δ ppm, CDCl₃): 1.56 (9H, s), 5.22(2H, s), 5.37 (2H, s), 7.04 (1H, dd), 7.33-7.42 (10H, m), 7.97 (1H, d),8.14 (1H, d), 8.45 (1H, d), 8.60 (1H, d), 8.65 (1H, d), 11.01 (1H, s),11.11 (1H, s).

Then, from 1.17 g (1.69 mmol) of the resultant sulfonylurea product, inthe same way, 404 mg (yield 60%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.89 (1H, d),7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 7.98 (1H, d), 8.51 (1H, s),11.51 (1H, s).

Example 27 Synthesis of4-[(7-methoxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid(Compound 27)

500 mg (1.23 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg(1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 15 mg (yield 3.1%: 4steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.82 (3H,s), 6.58 (1H, s), 6.80 (1H, d), 7.16 (1H, d), 7.56 (1H, s), 7.80 (1H,d), 7.90 (1H, d), 11.49 (1H, s).

Example 28 Synthesis of(±)-7-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-oxo-1H,3H-quinoline-3-carboxylicacid (Compound 28)

400 mg (1.23 mmol) of(±)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide and 468 mg(1.23 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 649 mg (yield 86%) of8-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid t-butyl ester. Properties: colorless amorphous, PMR (δppm, CDCl₃): 1.32 (9H, s), 3.18-3.30 (2H, m), 3.54 (1H, m), 5.35 (2H,s), 6.85 (1H, m), 7.00 (1H, m), 7.35-7.39 (5H, m), 7.87-7.96 (3H, m),8.47 (1H, m), 8.78 (1H, br), 10.92 (1H, br).

Then, from 640 mg (1.04 mmol) of the resultant sulfonylurea product, inthe same way, 258 mg (yield 55%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 3.23-3.31 (2H,m), 3.59 (1H, t), 7.07 (1H, d), 7.12 (1H, s), 7.25 (1H, d), 7.86 (1H,d), 7.96 (1H, d), 7.98 (1H, d), 10.84 (1H, s), 11.60 (1H, s).

Example 29 Synthesis of(±)-6-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-3-oxo-1,4-benzoxazine-2-carboxylicacid (Compound 29)

300 mg (0.91 mmol) of(±)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazin-6-sulfonamide and 349 mg(0.91 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 417 mg (yield 74%) of5-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylicacid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm,DMSO-d₆): 1.29 (9H, s), 5.37 (2H, s), 5.42 (2H, s), 7.19-7.26 (2H, m),7.37-7.57 (7H, m), 7.97 (1H, d), 8.25 (1H, d), 10.27 (1H, s), 11.25 (1H,s), 12.22 (1H, br).

Then, from 417 mg (0.68 mmol) of the resultant sulfonylurea product, inthe same way, 100 mg (yield 32%: 3 steps) of the above-identifiedcompound was obtained. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 5.47 (1H, s),7.11 (1H, s), 7.24 (1H, d), 7.29 (1H, d), 7.76 (1H, s), 7.78 (1H, d),7.86 (1H, d), 11.25 (1H, s), 11.62 (1H, s).

Example 30 Synthesis of4-[(7-hydroxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid(Compound 30)

620 mg (1.53 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 550 mg(1.51 mmol) of benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 25 mg (yield 4%: 4steps) of the above-identified compound. Properties: colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 6.48 (1H,s), 6.61 (1H, d), 7.14 (1H, d), 7.51 (1H, s), 7.70 (1H, d), 7.90 (1H,d), 10.80 (1H, s), 11.39 (1H, s).

Example 31 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilicacid (Compound 31)

840 mg (1.86 mmol) of Compound 17 was dissolved in 8 ml of 1,4-dioxane,240 μl (2.79 mmol) of propionyl chloride was added dropwise, then theresultant mixture was stirred overnight at 60° C. An excess of water wasadded to the reaction solution and the mixture was extracted with ethylacetate. The organic layer thus obtained was washed, dried, andconcentrated to obtain a crude product of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilate.The obtained crude product was stirred at room temperature in 3 ml oftrifluoroacetic acid for 1 hour, then the reaction solution wasconcentrated in vacuo to obtain a crude product. This was washed bydiethyl ether to obtain 400 mg (yield 48%; 2 steps) of theabove-identified compound. Properties: colorless crystal, Meltingpoint: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 1.10 (3H, t),2.45 (2H, dd), 7.11 (1H, s), 7.24 (1H, d), 7.85 (1H, d), 7.88 (1H, d),8.17 (1H, d), 9.18 (1H, s), 11.07 (1H, s), 11.63 (1H, s).

Example 32 Synthesis of4-[(6-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid(Compound 32)

300 mg (0.74 mmol) of3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 310 mg(0.81 mmol) of benzyl 5-chloro-2-N-phenoxycarbonylanthranilate weretreated in the same way as in Example 17 to obtain 75 mg (yield 26%: 4steps) of the above-identified compound. Properties; colorless crystal,Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d₆): 7.13-7.20(2H, m), 7.56 (1H, s), 7.72 (1H, d), 7.82 (1H, s), 7.90 (1H, d), 11.68(1H, s).

Example 33 Synthesis of4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-methanesulfonylanthranilicacid (Compound 33)

200 mg (0.44 mmol) of Compound 17 was treated in the same way as inExample 3 to obtain 81 mg of t-butyl4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-methanesulfonylanthranilate.This was used to perform the same debutylation reaction to obtain 53 mg(yield 25%: 2 steps) of the above-identified compound. Properties:colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm,DMSO-d₆): 3.24 (3H, s), 7.11 (1H, s), 7.25 (1H, d), 7.85-7.91 (2H, m),8.23 (1H, d), 8.39 (1H, s), 11.05 (1H, br), 11.70 (1H, s).

Example 34 Synthesis of3-(3-aminobenzenesulfonyl)-7-chloro-2,4-(1H,3H)quinazolinedionmethanesulfonic acid salt (Compound 34)

2.15 g (6.10 mmol) of compound 12 was dissolved in 65 ml of THF and 0.4ml of methanesulfonic acid was added dropwise. To this solution, 200 mlof ether was added and the resultant precipate was filtered to obtain2.59 g (yield 95%) of the above-identified compound. Properties:colorless amorphous, PMR (δ ppm, DMSO-d₆): 2.35 (3H, s), 6.98 (1H, d),7.12 (1H, m), 7.25 (1H, m), 7.34 (2H, s), 7.43 (1H, m), 7.86 (1H, s),11.64 (1H, s).

Evaluation Example 1 Measurement of Chymase Inhibitory Activity

Human heart chymase was purified according to the method of Urata et al.(J. Biol. Chem., 1990, 265, 22348). The inhibitory activity of thequinazoline derivatives of the present invention with respect to chymasewas measured in the following manner. That is, the purified enzymesolution was diluted to a suitable concentration with 0.1Mtris-hydrochloride buffer (pH=7.5), 1M sodium chloride, and 0.01%TritonX-100 to In obtain an enzyme solution. A 10 mM dimethyl sulfoxide(hereinafter referred to as DMSO) solution of Suc-Ala-Ala-Pro-Phe-MCA(Peptide Institute) was diluted 20-fold at the time of use by 0.1Mtris-hydrochlorate, 1M sodium chloride, and 0.01% TritonX-100 to obtainthe substrate solution.

75 μl of the enzyme solution warmed to 30° C. was mixed with 5 μl ofDMSO solution of the test sample. The mixture was preincubated at 30° C.for 10 minutes. Next, 20 μl of a substrate solution warmed to 30° C. wasmixed with the test sample-enzyme mixture and incubated at 30° c. After10 minutes, 50 μl of 30% acetic acid was added to stop the enzymaticreaction. The amount of the AMC produced was quantified using afluorescent photometer. At the same time, a blind test was carried outby adding, instead of the test sample solution, 5 μl of DMSO andperforming the same reaction. The chymase inhibitory activity wasexpressed by a rate of inhibition, that is, the 50% inhibitionconcentration (IC₅₀), based on the blind test value.

The quinazoline derivatives of the present invention all stronglyinhibited human chymase at concentrations of 100 μm. The IC₅₀ values fortypical compounds are shown in table 1

TABLE 1 Example No. IC₅₀ value (μM) t_(1/2) (min)  1 0.36  78  2 0.14175  8 0.035  29 10 0.17 167 12 0.44 249 13 0.3  97 16 0.84 >240  170.14 260 18 0.14 103 21 0.34 — 22 0.3 104 24 0.32  79 27 4.0 263 291.7 >240  32 1.5  74 34 0.36 709

Evaluation Example 2 Test of Human Chymase Induced Vascular PermeabilityExacerbation Reaction

Wister male rats (body weight 200 to 220 g, Charles River Japan) wereused. In the backs of the rats from which the hair had been shaved off,100 μl (20 mU: 1U being amount of enzyme for producing 1 nmol of AMC in1 minute from Suc-Ala-Ala-Pro-Phe-MCA at pH7.5 and 30° C.) of a solutionof the human chymase enzyme solution purified in evaluation Example 1diluted 100-fold by PBS (phosphate buffered saline) was injectedintracutaneously, then immediately thereafter a 0.5% (w/w) Evans Bluesolution was administered from the tail artery. After 30 minutes, therats were sacrificed by draining their blood under anesthesia with etherand the amount of dye leaking out to the back skin was measured. Theregion of the skin where the dye leaked out was cut off and 1.0 ml of 1NKOH solution was added and the resultant mixture was allowed to stand at37° C. overnight. Next, 4 ml of an acetone-0.6N phosphoric acid (13:5)mixture was added to extract the dye. The absorbance at 650 nm of thesupernatant was measured. The calibration curve for measurement of theamount of the dye leaked out was prepared by injecting Evans Bluesolution so as to give 10, 20, 30, 40, and 50 μg in the rat back skinand extracting the dye by the above method. Similarly, the amount of dyewhen administering intracutaneously 100 μl of the solution of the samecomposition but not containing human chymase was used as the control.

Next, 10 mg/kg of the compound of Example 18 was orally administered. 30minutes later, 100 μl (20 mU) of human chymase the same as the non-drugadministered group was injected intracutaneously and the amount of dyeleaked out similarly measured. The rate of suppression of the amount ofdye leakage due to the compound was calculated according to thefollowing calculation formula. The rate of suppression for the compoundof Example 18 was 64%.Rate of suppression of amount of leakage of dye (%)=[(amount of leakageof dye of compound administered group−amount of leakage of dye ofcontrol group)+(amount of leakage of dye of non-compound administeredgroup−amount of leakage of dye of control group)]×100.

It is known that vascular permeability is exacerbated when inflammationis caused by an inflammation causing substance. Further, suppression ofthe exacerbation of vascular permeability has become one of theindicators for evaluation of anti-inflammation agents. In general, it isknown that the histamine released by the degranulation of mast cellsexacerbate the vascular permeability. The fact that a quinazolinederivative suppresses the exacerbation of vascular permeability due tothe intracutaneous administration of chymase shows that the quinazolinederivative suppresses inflammation involving mast cells caused by thechymase.

Evaluation Example 3 Test of Stability in Human Plasma

Human plasma was diluted two-fold with 50 mM sodium phosphate buffer(pH=7.2) for use as the test plasma solution. The test sample was made aDMSO solution of 1 mM concentration.

198 μl of the above two-fold diluted plasma solution warmed to 37° C.was added to 2 μl of the test sample DMSO solution and the resultantmixture was stirred and incubated at 37° C. After 0, 5, and 15 minutes,800 μl of acetonitrile was mixed with the test sample-plasma mixture toremove the protein, then a centrifugation operation (12,000 rpm, 1minute) was carried out and the supernatant obtained. This was dilutedtwo-fold with distilled water and measured for of the test sample byHPLC analysis.

For the rate of recovery from the plasma, the rates of recovery atdifferent times were calculated based on a calibration line of the testsample in a DMSO standard solution. The half-life (t_(1/2)) in plasmawas calculated by exponential recurrence analysis from the rates ofrecovery of these different times. The half-lives (t_(1/2)) in plasma ofrepresentative compounds are shown in Table 1.

Preparation Example 1 Production of Tablets

100.0 g of Compound 1 was mixed with microcrystalline cellulose in anamount of 22.5 g and magnesium stearate in an amount of 2.5 g and thentabletized by a single-action type tabletizing machine to producetablets each containing 200 mg of Compound 1 and having a diameter of 9mm and a weight of 250 mg.

Preparation Example 2 Production of Granules

30 g of Compound 1 was mixed well with lactose in an amount of 265 g andmagnesium stearate in an amount of 5 g. The mixture was pressed molded,then pulverized and the granules sieved to obtain excellent 10% granulesof 20 to 50 mesh.

Preparation Example 3 Production of Suppository

Vitepsol H-15 (made by Dynamite Nobel Co.) was warmed to melt. To thiswas added Compound 1 to a concentration of 12.5 mg/ml. This washomogeneously mixed, then was added in 2 ml amounts to a rectalsuppository mold and cooled to obtain rectal suppositories eachcontaining 25 mg of the Compound 1.

INDUSTRIAL APPLICABILITY

The quinazoline derivative of the present invention inhibits chymase andfurther suppresses the exacerbation of vascular permeability induced bychymase, and therefore, is useful as a medicament for the prevention ortreatment of allergic diseases or rheumatic diseases or cardiac andcirculatory system diseases arising due to the abnormal exacerbation ofangiotensin II production. Examples of such diseases are inflammatorydiseases for which mast cells are predicted as being closely related,for example, bronchial asthma, eczema, atopic dermatitis, mastocytosis,scleriasis, rheumatoid arthritis, cardiac and circulatory systemdiseases due to the abnormal exacerbation of Ang ii production, forexample, cardiac insufficiency, hypercardia, stasis cardiac diseases,hypertension, arteriosclerosis, peripheral circulatory disorders,revasoconstriction after PTCA, diabetic renal disorders or non-diabeticrenal disorders, coronary diseases including myocardial infarction,angioendothelia, or vascular disorders accompanying arterialization oratheroma.

1. A quinazoline derivative having the following formula (1) or apharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group: R¹ represents (a) hydroxylgroup, (b) an amino group, (c) a C₁ to C₄ lower alkylamino group whichmay be substituted with a COOH group, (d) a C₇ and C₁₀ loweraralkylamino group which may be substituted with a COOH group, (e) anamino group acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a COOH group, (f) an amino group acylated with anaromatic ring carboxylic acid which may be substituted with a COOHgroup, (g) an amino group acylated with a heteroaromatic ring carboxylicacid which may be substituted with a COOH group, (h) an amino groupsulfonylated with a C₁ to C₄ lower alkanesulfonic acid which may besubstituted with a COOH group, (i) an amino group sulfonylated with anaromatic ring sulfonic acid which may be substituted with a COOH group,(j) an amino group sulfonylated with a heteroaromatic ring sulfonic acidwhich may be substituted with a COOH group, (k) a C₁ to C₄ lower alkylgroup substituted with a COOH group, or (l) a C₂ to C₄ lower alkenylgroup which may be substituted with a COOH group; R² represents (a) a C₁to C₄ lower alkyl group substituted with a COOH group, a halogen atom, aC₁ to C₄ lower alkoxy group, an amino group, a methylamino group, adimethylamino group, a carboxymethylamino group or a carboxyethylaminogroup, (b) a halogen atom, (c) a hydroxyl group, (d) a C₁ to C₄ loweralkoxyl group, (e) an amino group, (f) a C_(1 to C) ₄ lower alkylaminogroup which may be substituted with a COOH group, a halogen atom or a C₁to C₄ lower alkoxy group, (g) a C₇ to C₁₂ aralkylamino group which maybe substituted with a COOH group, a halogen atom or a C₁ to C₄ loweralkoxy group, (h) an amino group acylated with a C₁ to C₄ loweraliphatic acid which may be substituted with a COOH group, (i) an aminogroup acylated with an aromatic ring carboxylic acid which may besubstituted with a COOH group, (j) an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with a COOHgroup, (k) an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a COOH group, (l) anamino group sulfonylated with an aromatic ring sulfonic acid which maybe substituted with a COOH group, (m) an amino group sulfonylated with aheteroaromatic ring sulfonic acid which may be substituted with a COOHgroup, or (n) a COOH group or R³ represents (a) a hydrogen atom, (b) aC₁ to C₄ lower alkyl group which may be substituted with a COOH group, ahalogen atom, a C₁ to C₄ lower alkoxy group, an amino group, amethylamino group, a dimethylamino group, a carboxymethylamino group ora carboxyethylamino group, (c) a halogen atom, (d) a hydroxyl group, (e)a C₁ to C₄ lower alkoxyl group, (f) an amino group, (g) a C₁ to C₄ loweralkylamino group which may be substituted with a COOH group, a halogenatom or a C₁ to C₄ lower alkoxy group, (h) a C₇ to C₁₂ aralkylaminogroup which may be substituted with a COOH group, a halogen atom or a C₁to C₄ lower alkoxy group, (i) an amino group acylated with a C₁ to C₄lower aliphatic acid which may be substituted with a COOH group, (j) anamino group acylated with an aromatic ring carboxylic acid which may besubstituted with a COOH group, (k) an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with a COOHgroup, (l) an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a COOH group, (m) anamino group sulfonylated with an aromatic ring sulfonic acid which maybe substituted with a COOH group, (n) an amino group sulfonylated with aheteroaromatic ring sulfonic acid which may be substituted with a COOHgroup, or (o) a COOH group or when the ring A is benzene ring, R¹ and R²may form, together with the substituting benzene ring, (a) atetrahydroquinoline ring or (b) a benzoxazine ring which may besubstituted with a COOH group and in which the carbon atom in the ringmay form a carbonyl group and R³ is the same as defined above; and Xrepresents (a) a hydrogen atom, (b) a C₁ to C₄ lower alkyl group, (c) aC₁ to C₄ lower alkoxy group, (d) a halogen atom, (e) a hydroxyl group,(f) an amino group, or (g) a nitro group.
 2. A quinazoline derivative ora pharmaceutically acceptable salt thereof as claimed in claim 1,wherein, in the formula (1), R¹ is a hydroxyl group, an amino group, aC₁ to C₄ lower alkylamino group substituted with a COOH group, or anamino group acylated with a C₁ to C₄ lower aliphatic acid substitutedwith a COOH group.
 3. A quinazoline derivative or a pharmaceuticallyacceptable salt thereof as claimed in claim 1, wherein, in the formula(1), R² is a COOH group.
 4. A quinazoline derivative or apharmaceutically acceptable salt thereof as claimed in claim 1, whereinR³ in the formula (1) is a hydrogen atom.
 5. A pharmaceuticalcomposition comprising as an effective ingredient a pharmaceuticallyeffective amount of a quinazoline derivative or the pharmaceuticallyacceptable salt thereof according to claim 1 and a pharmaceuticallyacceptable carrier therefor.
 6. A chymase composition inhibitor havingas an effective ingredient a quinazoline derivative or itspharmaceutically acceptable salt according to claim 1, and apharmaceutically acceptable carrier therefor.
 7. A method for treatmentof allergic diseases or rheumatic diseases comprising administering to apatient in need of such treatment an effective amount of a quinazolinederivative or salt thereof according to claim
 1. 8. A method fortreatment of bronchial asthma, eczema, atopic dermatitis, mastocytosis,scleriasis or rheumatoid arthritis comprising administering to a patientin need of such treatment an effective amount of a quinazolinederivative or salt thereof according to claim
 1. 9. A method fortreatment of cardiac and circulatory system diseases due to the abnormalexacerbation of Angiotensin II production comprising administering to apatient in need of such treatment an effective amount of a quinazolinederivative or salt thereof according to claim
 1. 10. A method fortreatment of cardiac insufficiency, hypercardia, stasis cardiacdiseases, hypertension, arteriosclerosis, peripheral circulatorydiseases, revasoconstriction after PTCA, diabetic renal disorders ornon-diabetic renal disorders, cardiac infarction, angioendothelia orvascular disorders accompanying arterialization and atheroma comprisingadministering to a patient in need of such treatment an effective amountof a quinazoline derivative or salt thereof according to claim
 1. 11. Apharmaceutical composition comprising as an effective ingredient apharmaceutically effective amount of a quinazoline derivative or apharmaceutically acceptable salt thereof as claimed in claim 2, and apharmaceutically acceptable carrier therefor.
 12. A pharmaceuticalcomposition comprising as an effective ingredient a pharmaceuticallyeffective amount of a quinazoline derivative or a pharmaceuticallyacceptable salt thereof as claimed in claim 3, and a pharmaceuticallyacceptable carrier therefor.
 13. A pharmaceutical composition comprisingas an effective ingredient a pharmaceutically effective amount of aquinazoline derivative or a pharmaceutically acceptable salt thereof asclaimed in claim 4, and a pharmaceutically acceptable carrier therefor.14. A quinazoline derivative having the following formula (1) and apharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group: R¹ represents (a) hydroxylgroup, (b) a C₁ to C₄ lower alkylamino group which may be substitutedwith a COOH group, (c) a C₇ and C₁₀ lower aralkylamino group which maybe substituted with a COOH group, (d) an amino group acylated with a C₁to C₄ lower aliphatic acid which may be substituted with a COOH group,(e) an amino group acylated with an aromatic ring carboxylic acid whichmay be substituted with a COOH group, (f) an amino group acylated with aheteroaromatic ring carboxylic acid which may be substituted with a COOHgroup, (g) an amino group sulfonylated with a C₁ to C₄ loweralkanesulfonic acid which may be substituted with a COOH group, (h) anamino group sulfonylated with an aromatic ring sulfonic acid which maybe substituted with a COOH group, (i) an amino group sulfonylated with aheteroaromatic ring sulfonic acid which may be substituted with a COOHgroup, (j) a C₁ to C₄ lower alkyl group substituted with a COOH group,or (k) a C₂ to C₄ lower alkenyl group which may be substituted with aCOOH group; R² and R³ may be the same or different and represent (a) ahydrogen atom, (b) a C₁ to C₄ lower alkyl group which may be substitutedwith a COOH group, a halogen atom, a C₁ to C₄ lower alkoxy group, anamino group, a methylamino group, a dimethylamino group, acarboxymethylamino group or a carboxyethylamino group, (c) a halogenatom, (d) a hydroxyl group, (e) a C₁ to C₄ lower alkoxyl group, (f) anamino group, (g) a C₁ to C₄ lower alkylamino group which may besubstituted with a COOH group, a halogen atom or a C₁ to C₄ lower alkoxygroup, (h) a C₇ to C₁₂ aralkylamino group which may be substituted witha COOH group, a halogen atom or a C₁ to C₄ lower alkoxy group, (i) anamino group acylated with a C₁ to C₄ lower aliphatic acid which may besubstituted with a COOH group, (j) an amino group acylated with anaromatic ring carboxylic acid which may be substituted with a COOHgroup, (k) an amino group acylated with a heteroaromatic ring carboxylicacid which may be substituted with a COOH group, (l) an amino groupsulfonylated with a C₁ to C₄ lower alkanesulfonic acid which may besubstituted with a COOH group, (m) an amino group sulfonylated with anaromatic ring sulfonic acid which may be substituted with a COOH group,(n) an amino group sulfonylated with a heteroaromatic ring sulfonic acidwhich may be substituted with a COOH group, or (o) a COOH group or whenthe ring A is benzene ring, R¹ and R² may form, together with thesubstituting benzene ring, (a) a tetrahydroquinoline ring or (b) abenzoxazine ring which may be substituted with a COOH group and in whichthe carbon atom in the ring may form a carbonyl group and R³ is the sameas defined above; and X represents (a) a hydrogen atom, (b) a C₁ to C₄lower alkyl group, (c) a C₁ to C₄ lower alkoxy group, (d) a halogenatom, (e) a hydroxyl group, (f) an amino group, or (g) a nitro group.15. A quinazoline derivative or a pharmaceutically acceptable saltthereof as claimed in claim 1, wherein said compound is selected fromthe group consisting of3-(3-amino-4-chlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,3-(4-amino-3,5-dichlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,4-[(7-chloro-2,4(1H,3H)quinazolinedion-3-yl)sulfonyl]anthranilic acid,4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acidmonosodium salt,3-(3-amino-4-methoxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,5-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid,4-[(7-methoxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid,4-[(7-hydroxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acidand 4-[(6-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilicacid.
 16. A pharmaceutical composition comprising as an effectiveingredient a pharmaceutically effective amount of a quinazolinederivative or a pharmaceutically acceptable salt thereof according toclaim 14 and a pharmaceutically acceptable carrier therefore.
 17. Achymase composition inhibitor having as an effective ingredient aquinazoline derivative or a pharmaceutically acceptable salt thereofaccording to claim 14 and a pharmaceutically acceptable carriertherefore.